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Abstract

The heart and the vasculature are key targets of angiotensin (Ang) II. In this regard, Ang II acting via Ang II type 1 (AT1)-receptors induces hypertension, cardiac hypertrophy and vascular injury. Since AT1-receptor stimulation have been shown to activate the mitogen activated protein kinase (MAPK) p38 leading to hypertrophy, migration and remodelling in cardiomocytes and vascular smooth muscle cells (VSMC)s in vitro, the MAPK p38 is considered as a major contributor in Ang II mediated cardiac and vascular injury. In order to investigate its role in Ang II dependent hypertension, we generated mice lacking p38alpha only in VSMC and cardiomyocytes (p38KO) using Cre-Loxp technology with a KISM22-cre transgene on a Bl6/C57 background. The specificity of p38alpha deletion was verified by western blot analysis. While cardiac function did not differ between both groups, blood pressures (BPs) were significantly lower under baseline conditions in p38KO mice compared to controls (106.4±5.2 vs. 123.6±5.4 mmHg; p<0.05). To test whether p38KO mice were protected from hypertensive heart failure and vascular injury, we infused Ang II (1000ng/kg/min) for 2 weeks. Ang II infusion caused a significantly attenuated increase in BPs in p38KOs than in controls (117.9±9.7 vs. 148.0±18.8mmHg; p<0.001). This effect could not be explained by an attenuated vascular response to Ang II in p38KOs, as acute pressor responses to Ang II in vivo and in the isolated perfused kidney as well as changes in renal blood flow were not attenuated in p38KO compared to controls. Surprisingly, in p38KOs, chronic Ang II infusion caused exaggerated cardiac fibrosis and severe dilated cardiomyopathy which was already apparent on day two after Ang II infusion (ejection fraction: 26.6±8.5 (p38KO) vs. 60.8±9.6% (control); p<0.001, diastolic volume: 116.9±8.6 vs. 60.2±7.6μl, p<0.001; systolic volume: 88.9±10.3 vs. 24.6±6.7μl, p<0.001). In summary, these results suggest a divergent role of p38 in regulating blood pressure and in the pathogenesis of heart failure as Ang II induces blood pressure independent dilated cardiomyopathy in p38KO mice. However, more studies are necessary to reveal the underlying mechanism.